OLIGOSACCHARIDE STRUCTURE & FUNCTION IN RECOGNITION

低聚糖结构

• 批准号: 7825328
• 负责人: JACQUES U BAENZIGER
• 金额: $ 66.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825328
• 关键词: Acute-Phase Reaction; Address; Asialoglycoprotein Receptor; Avidity; Bacterial Infections; Binding; Biochemical Genetics; Biological; Blood; Blood Circulation; Blood Coagulation Factor; Carbohydrates; Carrier Proteins; Cell Count; Cell surface; Cells; Coagulation Process; Complement; Diagnostic; Endothelial Cells; Equilibrium; Estrogens; Excision; Foundations; Genetic Models; Glycoproteins; Grant; Growth Factor; Hemolysis; Hormones; Host Defense; Immunoglobulins; Infection; Inflammation; Inflammatory; Injury; Knockout Mice; Ligands; Link; Liver; Mannose; Mediating; Metabolic; Methods; Molecular; Mus; Oligosaccharides; Pathologic; Physiological; Pituitary Gland; Plasma; Plasma Proteins; Pregnancy; Process; Production; Progress Reports; Protease Inhibitor; Protein Isoforms; Proteins; Proteomics; Regulation; Relative (related person); Reproduction; Reproductive Biology; Role; Sepsis; Specificity; Stress; Structure; System; Therapeutic; Time; Ursidae Family; Whole Organism; bacterial resistance; base; carbohydrate structure; cytokine; in vivo; insight; macrophage; pregnant; public health relevance; receptor; response; response to injury; septic

DESCRIPTION (provided by applicant): Over the 30 years' duration of this grant, this project has established a broad foundation for understanding the role of carbohydrate structures on glycoproteins. In this time our studies have defined 1) unique oligosaccharide structures as signatures found on specific plasma glycoproteins, 2) the mechanisms of recognition of these structures by carbohydrate-specific endocytic receptors, and 3) the functionally important in vivo biological consequences of this recognition. We have proceeded from determining at the molecular and cellular level the biologic basis of oligosaccharide recognition by these receptors, to delineating at the whole organism level the functional implications of such recognition. Our progress on how carbohydrate-specific endocytic receptor recognition systems clear particular glycoproteins from the circulation now culminates in a unique opportunity to take these studies to a new level of functional perspective. We have demonstrated by biochemical and genetic means that the Mannose/GalNAc-4-SO4-receptor (M/G4S-R) and the asialoglycoprotein-receptor (ASGP-R) mediate the respective clearance of glycoproteins that bear the N-linked oligosaccharide signatures of terminal GalNAc 4 SO4 and of terminal Sia12,6GalNAc. We have shown that the ASGP-R can bind glycoproteins bearing Sia12,6Gal. We hypothesize that glycoproteins bearing terminal Sia12,6Gal are in fact the major endogenous ligands for the ASGP-R and that the ASGP-R is a key regulator of the concentration of numerous plasma glycoproteins that have Sia12,6Gal termini. Preliminary studies support this proposed function. Our findings give a significant new functional identity to this receptor. We will now use genetic models and recently established proteomic methods to define the relative roles of the ASGP-R and M/G4S-R. We will determine how these receptors act, individually and in combination, to regulate levels of plasma glycoproteins based on their carbohydrate signatures, under physiologic as well as pathologic conditions ranging from regulation of estrogen production by pituitary glycoprotein hormones to the acute phase response to sepsis. These proposed studies utilize single and double receptor knockout mice 1) to address how production is balanced with clearance to regulate plasma levels of glycoproteins through recognition of their carbohydrate signatures, 2) to determine if perturbing this balance has an impact on biologic processes, and 3) to establish the molecular basis for generating isoforms of the M/G4S-R with differing carbohydrate signature specificities and determine the impact of such receptor isoforms on reproductive biology. The fundamental mechanistic information that we uncover will ultimately yield insights that can aid in evaluating changes in plasma proteins for both diagnostic and therapeutic purposes. Public Health Relevance: The levels of glycoproteins in the blood reflect a balance between their synthesis and removal. We have identified two major carbohydrate specific receptor systems in liver that help control the concentrations of many glycoproteins in the blood by determining their rates of removal. We will define how these receptors control the concentrations of hormones and inflammatory proteins during pregnancy and the response to injury.

描述（由申请人提供）：在该资助的30年期间，该项目为理解糖蛋白的碳水化合物结构的作用建立了广泛的基础。在这段时间里，我们的研究已经定义了1）独特的寡糖结构作为在特定血浆糖蛋白上发现的特征，2）碳水化合物特异性内吞受体识别这些结构的机制，以及3）这种识别的功能重要的体内生物学后果。我们已经着手从确定在分子和细胞水平上的生物学基础的寡糖识别这些受体，描绘在整个生物体水平上的功能的影响，这种识别。我们在碳水化合物特异性内吞受体识别系统如何从循环中清除特定糖蛋白方面的进展现在达到了一个独特的机会，将这些研究带到了一个新的功能视角水平。我们已经通过生物化学和遗传学手段证明，甘露糖/GalNAc-4-SO4-受体（M/G4S-R）和脱唾液酸糖蛋白受体（ASGP-R）介导了携带末端GalNAc-4 SO4和末端Sia12，6GalNAc的N-连接寡糖特征的糖蛋白的各自清除。我们已经证明ASGP-R可以结合带有Sia12，6Gal的糖蛋白。我们假设，携带末端Sia12，6Gal的糖蛋白实际上是ASGP-R的主要内源性配体，并且ASGP-R是具有Sia12，6Gal末端的许多血浆糖蛋白浓度的关键调节剂。初步研究支持这一拟议职能。我们的研究结果提供了一个重要的新功能的身份，这种受体。我们现在将使用遗传模型和最近建立的蛋白质组学方法来定义ASGP-R和M/G4S-R的相对作用。我们将确定这些受体如何单独或联合作用，根据其碳水化合物特征调节血浆糖蛋白水平，在生理和病理条件下，从垂体糖蛋白激素调节雌激素产生到脓毒症急性期反应。这些拟议的研究利用单和双受体敲除小鼠1）解决如何通过识别糖蛋白的碳水化合物特征来平衡糖蛋白的产生与清除以调节糖蛋白的血浆水平，2）确定扰乱这种平衡是否对生物过程产生影响，和3）建立产生M/G4S-亚型的分子基础，R与不同的碳水化合物签名特异性，并确定这种受体亚型对生殖生物学的影响。我们发现的基本机制信息最终将产生有助于评估血浆蛋白变化的见解，用于诊断和治疗目的。 公共卫生相关性：血液中糖蛋白的水平反映了它们的合成和去除之间的平衡。我们已经确定了肝脏中两个主要的碳水化合物特异性受体系统，通过确定其去除率来帮助控制血液中许多糖蛋白的浓度。我们将定义这些受体如何控制怀孕期间激素和炎症蛋白的浓度以及对损伤的反应。